The present invention is concerned with a series of novel polypeptide derivatives containing 5-amino-2,5-disubstituted-4-hydroxypentanoic acid residues, which are useful for inhibiting the angiotensinogencleaving action of the enzyme renin; and intermediates therefor, particularly N-alpha-[N-(t-butoxycarbonyl)phenylalanyl]-N(imidazole)-(t-butoxycarbonyl) histidine.
The proteolytic enzyme renin, which has a molecular weight of about 40,000, is produced in and secreted into the blood by the kidney. It is known to be active in vivo in cleaving the naturally-occurring plasma glycoprotein angiotensinogen. In the case of human angiotensinogen, cleavage is at the bond between the leucine (10th) and valine (11th) amino acid residues at the N-terminal end of the angiotensinogen: ##STR1## The circulating N-terminal decapeptide (angiotensin I) formed by the above cleaving action of renin is subsequently broken down by the body to an octapeptide known as angiotensin II. Angiotensin II is known to be a potent pressor substance, i.e. a substance that is capable of inducing a significant increase in blood pressure, and is believed to act by causing the constriction of blood vessels and the release of the sodium-retaining hormone aldosterone from the adrenal gland. Thus, the renin-angiotensinogen system has been implicated as a causative factor in certain forms of hypertension.
One means of alleviating the adverse effects of the functioning of the renin-angiotensinogen system is the administration of a substance capable of inhibiting the angiotensinogen-cleaving action of renin. A number of such substances are known, including antirenin antibodies, pepstatin and naturally-occurring phospholipid compounds. European Patent Application No. 77,028 discloses a series of renin-inhibiting polypeptide compounds having a non-terminal statine (Sta; 4-amino-3-hydroxy-6-methylheptanoic acid) or statine derivative. Including Sta, the vast majority of compounds exemplified contain 6 or more aminoacid residues. Exemplary of the few shortest chains there disclosed are:
Acetyl-Phe-His-Sta-Leu-Phe-NH.sub.2, and PA1 t-Butyloxycarbonyl-Phe-His-Sta-Leu-Phe-NH.sub.2. PA1 W is ##STR4## where R.sup.5 is phenyl, 1-naphthyl, 4-hydroxyphenyl, 4-methoxyphenyl, 4-imidazolyl, propyl or isopropyl; PA1 R.sup.1 and R.sup.2 are each independently hydrogen, (C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkenyl, phenyl, naphthyl, (C.sub.4 -C.sub.7)cycloalkyl (C.sub.4 -C.sub.7) cycloalkenyl, (C.sub.7 -C.sub.9)phenylalkyl, (C.sub.11 -C.sub.13)naphthylalkyl, (C.sub.5 -C.sub.10) (cycloalkyl)alkyl, (C.sub.5 -C.sub.10) (cycloalkenyl)alkyl, or one of said groups mono- or disubstituted on the aromatic ring with the same or different groups selected from (C.sub.1 -C.sub.3)alkyl, (C.sub.1 -C.sub.3)alkoxy, fluoro or chloro; and PA1 W.sup.3 is ##STR10## where R.sup.14 is ---NHCO.sub.2 CH.sub.2 CH.sub.2 C.sub.6 H.sub.5, ##STR11## or --CH.sub.2 NHCO.sub.2 C.sub.6 H.sub.5 ; R.sup.11 is hydrogen or t-butoxycarbonyl; and PA1 (a) R.sup.12 and R.sup.13 are taken separately and are each independently hydrogen, alkyl, phenyl, naphthyl, (C.sub.4 -C.sub.7)cycloalkyl, adamantyl (C.sub.7 -C.sub.9)phenylalkyl, (C.sub.11 -C.sub.13)naphthylalkyl or (C.sub.5 -C.sub.10) (cycloalkyl)alkyl, or R.sup.12 is hydrogen and R.sup.13 is ##STR12## p, q, r and Q are as defined above; Y.sup.1 is methyl, phenyl, --COOR.sup.18, --CONR.sup.9 R.sup.10, --CONHCOOCH.sub.2 C.sub.6 H.sub.5, --NHCOCH.sub.2 C.sub.6 H.sub.5, ##STR13## R.sup.7, R.sup.8, R.sup.9 and R.sup.10 are each independently as defined above; and PA1 R.sup.18 is an independent value of R.sup.7 other than hydrogen; or PA1 (b) R.sup.12 and R.sup.13 are taken together with the nitrogen to which they are attached to form a pyrrole, indoline, isoindoline, piperidine, 1,2,3,4-tetrahydro- quinoline, 1,2,3,4-tetrahydroisoquinoline, perhydroazepine, or morpholine ring system; and PA1 an intermediate compound of the formula ##STR14##
There are invariably at least two amino acid residues each side of statine. The di- or polypeptidyl-statyl group is invariably attached to a lipophilic amino acid, most often leucine. (See also U.S. Pat. Nos. 4,470,971 and 4,478,826).
European Patent Application No. 45,665 and U.S. Pat. No. 4,424,207 disclose a series of renin-inhibiting polypeptide derivatives of the formula ##STR2## where A is for example t-butoxycarbonyl, B is His or other basic aminoacyl group, D is Val, Ile or other liphophilic aminoacyl residue, E is Tyr, Phe, His or other aromatic aminoacyl residue, R.sup.a and R.sup.b are each isopropyl, isobutyl, benzyl or other lipophilic aminoacid type sidechain, and Y.sup.a is a terminal acid, ester or amide type group. Including the central 5-aminopentanoic acid residues, these compounds are invariably heptapeptides, i.e., N-tetrapeptidyl-5-aminopentanoyllipophilic aminoacyl-aromatic amino-acid derivatives.